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De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia
  1. Esther R Berko1,
  2. Megan T Cho2,
  3. Christine Eng3,
  4. Yunru Shao3,4,
  5. David A Sweetser5,
  6. Jessica Waxler5,
  7. Nathaniel H Robin6,
  8. Fallon Brewer6,
  9. Sandra Donkervoort7,
  10. Payam Mohassel7,
  11. Carsten G Bönnemann7,
  12. Martin Bialer8,
  13. Christine Moore8,
  14. Lynne A Wolfe9,10,
  15. Cynthia J Tifft9,10,
  16. Yufeng Shen11,
  17. Kyle Retterer2,
  18. Francisca Millan2,
  19. Wendy K Chung1,12
  1. 1Department of Pediatrics, Columbia University Medical Center, New York, New York, USA
  2. 2GeneDx, Gaithersburg, Maryland, USA
  3. 3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  4. 4Texas Children's Hospital, Houston, Texas, USA
  5. 5Massachusetts General Hospital, Boston, Massachusetts, USA
  6. 6University of Alabama at Birmingham, Birmingham, Alabama, USA
  7. 7National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
  8. 8Cohen Children's Medical Center of NY, New Hyde Park, New York, USA
  9. 9Office of the Clinical Director, National Institutes of Health, Bethesda, Maryland, USA
  10. 10Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland, USA
  11. 11Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, New York, USA
  12. 12Department of Medicine, Columbia University Medical Center, New York, New York, USA
  1. Correspondence to Dr Wendy K Chung, Columbia University Medical Center, 10032 New York, USA; wkc15{at}


Background The causes of intellectual disability (ID) are diverse and de novo mutations are increasingly recognised to account for a significant proportion of ID.

Methods and results In this study, we performed whole exome sequencing on a large cohort of patients with ID or neurodevelopmental delay and identified four novel de novo predicted deleterious missense variants in HECW2 in six probands with ID/developmental delay and hypotonia. Other common features include seizures, strabismus, nystagmus, cortical visual impairment and dysmorphic facial features. HECW2 is an ubiquitin ligase that stabilises p73, a crucial mediator of neurodevelopment and neurogenesis.

Conclusion This study implicates pathogenic genetic variants in HECW2 as potential causes of neurodevelopmental disorders in humans.

  • intellectual disability
  • whole exome sequencing
  • de novo
  • HECW2
  • neurodevelopmental delay

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